• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Molecular basis of prostanoid receptor-mediated pathogenesis and its drug application

Research Project

Project/Area Number 12557211
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Biological pharmacy
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

ICHIKAWA Atsushi  Kyoto Univ., Grad. Sch. of Pharmaceu. Sci., Professor, 薬学研究科, 教授 (10025695)

Co-Investigator(Kenkyū-buntansha) MARUYAMA Takayuki  Ono Phamaceu. Co. Ltd., Discovery Research Labs.l, Researcher, 創薬第1研, 研究員
HAMANAKA Nobuyuki  Ono Phamaceu. Co. Ltd., Dept. of Med. Chem., Principal Researcher, 薬化学研, 研究員
SUMGIMOTO Yukihiko  Kyoto Univ., Grad. Sch. of Pharmaceu. Sci., Associate Professor, 薬学研究科, 助教授 (80243038)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥13,300,000 (Direct Cost: ¥13,300,000)
Fiscal Year 2001: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 2000: ¥8,300,000 (Direct Cost: ¥8,300,000)
Keywordsprostaglandin / receptor subtypes / signal transduction / gene targeting / cycloxygenase-2 / colon cancer / colitis / receptor blocker / 喘息 / 遺伝子欠損マウス / 好中球 / 分娩 / シクロオキシゲナーゼ
Research Abstract

Results obtained by Kyoto University Group
(1) Elucidation of patho-physiological roles of prostanoids by using each receptor-deficient mice :
We found that EP2 deficiency attenuated intestinal polyp formation both in number and size in-Apc KO mice. We also showed acceleration of COX-2, EP2 and VEGF expression in the intestinal polyps of wild-type mice, but faint expression of COX-2 or VEGF in those of EP2 and Ape double-knockout mice, suggesting that there exists positive feedback regulation between COX-2 and EP2. We introduced dextransulfate (DSS)-induced colitis model into EP-deficient mice. As a result, only EP4-deficient mice showed severe colitis upon 3%DSS treatment that did not induce significant colitisin wild-type mice. EP4 has been shown to promote epithelial regeneration and to inhibit activation of leukocytes and lymphocytes.
(2) The new signal transduction pathway exerted by prostanoid receptor EP3 :
EP3 has been shown to be coupled to Gi activity, inhibition of adenylate cyc … More lase. EP3 has multiple isoforms that are different in their C-terminal structure and in their agonist-dependent Gi activity. We found that EP3 receptors expressed in COS-7 cells showed augmentation of other receptor-stimulated Gs activity in an agonist-dependent manner. The superactivation of Gs by EP3 receptors was not affected by the treatment of pertussis toxin, suggesting that the superactivation is not Gi-mediated. The EP3 agonist-dependent supeactivation of Gs is observed in any type of mouse EP3 receptor isoforms, irrespective of C-termnal structure of EP3 receptor. This EP3 signaling may reflect some aspects of the physiological function of PGE2, such as pain sensation.]
Results obtained by Ono Pharmaceutical Co. Group
(3) Development of EP4 receptor-specific ligands :
Improvement of EP4-receptor selectivity and the agonist activity by introduction of heteroatoms into the alpha chain of PGE1 was investigated. Of the compounds produced, 16-phenyl-omega-tetranor-3,7-dithiaPGE1 possessing moderate EP4-receptor selectivity and agonist activity, was identified as a new chemical lead for further optimization by modification of the aromatic moiety Based on the information, we also successfully generated an EP4-specific antagonist with a high selectivity. Less

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Yamane, H., et al.: "Prostaglandin E2 receptor, EP2 and EP4, differentially modulate TNF-α and IL-6 production induced by lipopolysaccharide in mouse peritoneal neutrophils"Biochem. Biophys. Res. Commun.. 278. 224-228 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Matsuoka, T., et al.: "Prostaglandin D2 as a mediator of allergic asthma"Science. 287. 2013-2017 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ikegami, R., et al.: "The expression of prostaglandin E receptors EP2 and EP4 and their different regulation by LPS in C3H/HeN peritoneal macrophages"J. Immunol.. 166. 4689-4696 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sonoshita, M., et al.: "Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ716 knockout mice"Nature Medicine. 7. 1048-1051 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kabashima, K., et al.: "Protective role of PGE receptor subtype-EP4 in intestinal inflammation"J. Clin. Invest.. (in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hatae, N., et al.: "Augmentation of Receptor-Mediated Adenylyl Cyclase Activity by Gi-Coupled Prostaglandin Receptor Subtype EP3 in a Gβγ Subunit-Independent Manner"Biochem. Biophys. Res. Commun.. 290. 162-168 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamane. H., et al.: "Prostaglandin E2 receptor, Ep2 and EP4, differentially modulate TNF-α and IL-6 production induced by lipopolysaccharide in mouse peritoneal neutrophils"Biochem. Biophys. Res. Commun.. 278. 224-228 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Matsuoka, T., et al.: "Prostaglandin D2 as a mediator of allergic asthma"Science. 287. 2013-2017 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ikegami, R., et al.: "The expression of prostaglandin E receptors EP2 and EP4 and their different regulation by LPS in C3H/HeN peritoneal macrophages"J. Immunol.. 166. 4689-4696 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sonoshita, M., et al.: "Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ716 knockout mice"Nature Medicine. 7. 1048-1051 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kabashima, K., et al.: "Protective role of PGE receptor subtype-EP4 in intestinal inflammation"J. Clin. Invest.. (in press). (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hatae, N., et al.: "Augmentation of Receptor-Mediated Adenylyl Cyclase Activity by Gi-Coupled Prostaglandin Receptor Subtype EP3 in a Gβγ Subunit-Independent Manner"Biochem. Biophys. Res. Commun.. 290. 162-168 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sonoshita M, Takaku K, Sasaki, Sugimoto Y et al.: "Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ716"Nature Medicine. 7. 1048-1051 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kabashima Saji T, Murata T et al.: "Protective role of PGE receptor subtype-EP4 in intestinal inflammation"J. Clin. Invest.. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Torri E, Segi E, Sugimoto Y, et al.: "Expression of prostaglandin E2 receptor subtypes in mouse hair follicles"Biochem. Biophys. Res. Commun.. 122. 145-155 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hatae, N., Yamaoka, K., Sugimoto, et al.: "Augmentation of Receptor-Mediated Adenylyl Cyclase Activity by Gi-Coupled Prostaglandin Receptor Subtype EP3 in a GβγSubunit-Independent Manner"Biochem. Biophys. Res. Commun.. 290. 162-168 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ueno A, Matsumoto H, Naraba H, et al.: "Major roles of prostanoid receptors IP and EP(3) in endotoxin-induced enhancement of pain perception"Biochem. Pharmacol.. 62. 157-160 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ma H, Hara A, Xiao CY, et al.: "Increased bleeding tendency and decreased susceptibility to thromboembolism in mice lacking the prostaglandin E receptor subtype EP3"Circulation. 104. 1176-1180 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ikegami,R., et al.: "The expression of prostaglandin E receptors EP2 and EP4 and their different regulation by LPS in C3H/HeN peritoneal macrophages."J.Immunol.. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yamane,H., et al.: "Prostaglandin E2 receptor, EP2 and EP4, differentially modulate TNF-α and IL-6 production induced by lipopolysaccharide in mouse peritoneal neutrophils."Biochem.Biophys.Res.Commun.. 278. 224-228 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Matsuoka,T., et al.: "Prostaglandin D2 as a mediator of allergic asthma."Science. 287. 2013-2017 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sugimoto,Y., et al.: "Distribution and function of prostanoid receptors : studies from knockout mice."Jpn.J.Pharmacol.. 83. 279-285 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Croy,B.A., et al.: "Prolonged gestation dose not extend survival of uterine natural killer lymphocytes in mice deleted in the receptor for prostaglandin F_<2α>."J.Reprod.Immunol.. 46. 125-129 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tsuboi,K., et al.: "Uterine expression of prostaglandin H_2 synthase in late pregnancy and during parturition in prostaglandin F receptor-deficient mice."Endocrinology. 141. 315-324 (2000)

    • Related Report
      2000 Annual Research Report

URL: 

Published: 2000-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi